Inflammation is a ubiquitous response to acute or chronic tissue injury. Reactive oxygen and nitrogen species (ROS/RNS) generated during inflammation are causal to or can exacerbate pathogenesis of Alzheimer disease, atherosclerosis, cancer, ischemia-reperfusion injury in stroke, inflammatory bowel disease, myocardial infarction, and organ transplantation. Generation of the majority of ROS species is driven by heavy metal catalyzed oxidation reactions and enzymatically by myeloperoxidase (MPO). MPO is a heme-containing enzyme that mediates production of hypochlorious acid (HOCl/OCl−) from chloride ion (Cl−) and hydrogen peroxide (H2O2). MPO can accommodate and oxidize a number of small molecule substrates that bind to the active site displacing water molecules.
MPO has been shown to be a biomarker of myocardial infarction (MI) and coronary artery disease, due to the central role of MPO-dependent protein modification in the pathogenesis cardiovascular diseases. In atherosclerosis, low density lipoprotein (LDL) particles are oxidized by HOCl, chloramines, phenoxyl radical intermediates, peroxynitrite (ONOO−) and MPO-dependent nitrogen dioxide (NO2) production, driving lipid-laden macrophages to become atherosclerotic foam cells; the core of vulnerable plaques.
Imaging of MPO function and ROS generation in cells and animal models of human diseases has been hampered by the lack of probes with appropriate pharmacokinetics, suitable emission wavelengths to overcome tissue auto-fluorescence, and adequate specificity for relevant ROS. Tailoring of optical imaging probes for certain ROS/RNS species have been attempted with varied success for measuring nitric oxide, superoxide/OH, H2O2, ONOO−, and HOCl. However, in vivo use of these probes is not practical, because most are small molecules with unfavorable washout kinetics, have poor dye properties, and/or are activated by numerous ROS. Therefore, there exists a need for new ways for monitoring ROS/RNS generation.